BioWorld International Correspondent

LONDON - A new era in breast cancer treatment might be about to begin, with physicians able to offer patients a genetic test to determine which types of chemotherapy are likely to be most effective against their tumors.

The test would measure levels of expression of BRCA1, the gene that, when mutated, confers a high risk of developing breast cancer. Initial studies suggest that the BRCA1 protein can influence a cell's response to different categories of chemotherapeutic drugs.

Researchers in Northern Ireland have already embarked on a pilot study to find out whether they can link patients' clinical responses to chemotherapy with their BRCA1 status. If the study delivers promising results, a nationwide research project will be set up to confirm the findings.

Richard Kennedy, clinical research fellow at the Cancer Research Centre of Queen's University Belfast, told BioWorld International: "If we can substantiate our initial results, we will be able to target chemotherapy better. If you were able to tell that a patient's tumor is resistant to a certain therapy, then you could avoid giving her that drug, from which she would gain no benefit but might suffer unpleasant side effects."

Paul Harkin, senior oncology lecturer at the university, who led the study, described the results as "quite dramatic" and "very exciting." As a result, "BRCA1 status may be invaluable in deciding which type of chemotherapy to use," he said.

An account of the study appears in the October issue of Cancer Research, titled "BRCA1 functions as a differential modulator of chemotherapy-induced apoptosis."

About half of all cases of familial breast cancer are due to mutation of BRCA1. Recently, research has shown that in about a third of sporadic cases of breast cancer, expression of BRCA1 is lower than normal.

The Northern Ireland team already knew that cells from tumors with mutations in BRCA1 were resistant to drugs such as paclitaxel, which work by binding to the microtubules of dividing cells. As they report in Cancer Research, they have now shown that breast cancer cells making functional BRCA1 protein were up to 1,000 times more sensitive to drugs such as paclitaxel than those lacking BRCA1. Similarly, cells making BRCA1 were between 10 and 1,000 times more resistant than cells without it to drugs that work by inducing breaks in double-stranded DNA, such as cisplatin and etoposide.

Kennedy said the finding was particularly timely because of the increasing trend, already well established in the U.S., to add paclitaxel to the regime of drugs given to women having adjuvant therapy after initial surgery to treat breast cancer.

The team is recruiting women for a pilot study aimed at finding out whether their initial results will be borne out clinically. Looking at 50 patients with locally advanced breast cancer, the researchers first take a biopsy of the tumor and test it for the level of BRCA1 expression. Each patient then receives chemotherapy. Twenty-four hours after the first biopsy, another one will be taken and tested again for BRCA1 expression, as well as for signs of cell death. The size of the patients' tumors will be measured before and after the course of chemotherapy.

The observations in Cancer Research fit well with what is known about the biological role of BRCA1, Kennedy said.

"BRCA1 is a gene involved in the repair of damage to DNA. What this work suggests is that if a patient has a tumor with abnormal BRCA1, then the correct treatment would be a DNA-damaging drug such as cisplatin or etoposide, avoiding use of antimicrotubule drugs such as paclitaxel. If the tumor had a high level of BRCA1, however, then you might want to avoid the DNA-damaging drugs because there is a good DNA repair system in place, and give a drug such as paclitaxel."

Commenting on the paper, Robert Souhami, director of clinical research at Cancer Research UK, which helped fund the study, said: "It's intriguing that a single gene should have such important effects on the way cancer cells respond to treatment. We must now await results from clinical trials with patients to make sure that the expression of the gene really does predict the likelihood of responding to certain drugs. But there is no doubt that this discovery could have significant implications for the future of breast cancer treatment."

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